Project Summary/Abstract Chronic leg and foot ulcers are considerably slow healing, lasting on average 12 to 13 months. They are commonly associated with systemic diseases and conditions with impaired wound healing such as diabetes and vascular disease. For example, diabetic leg ulcers are an example of a difficult to heal chronic wound associated with diabetes and venous leg ulcers are a chronic wound attributed to poor blood circulation. A hallmark of these chronic wounds is out of balance inflammation caused by elevated levels of proteases, reactive oxidative species (ROS) and instances of infection. Herein is proposed the design and evaluation of hydrogels that target multiple aspects of a toxic inflammatory process. These hydrogels are designed to counteract the high levels of ROS, proteolytic activity and microbial infection present in chronic wounds. Hydrogels comprised of polydopamine and curcumin will be developed to impart antioxidant activity. Various strategies will be examined to counteract proteolytic matrix metalloproteinase (MMP) activity. Zn2+ is responsible for the catalytic activity of MMP and binding the metal is a well-established method to reduce its proteolytic activity. Curcumin is an antioxidant with zinc chelation ability that has been shown to reduce MMP activity and improve wound healing. We will synthesize water-soluble degradable curcumin polymers for incorporation within hydrogels. We propose these curcumin hydrogels will lower ROS and MMP activity. Polydopamine will be used to synthesize silver nanoparticles (AgNPs) within the hydrogels. AgNPs are well known for their antimicrobial properties but have also been demonstrated to inhibit MMP. A third strategy is to chemically modify hydrogels with bisphosphonate MMP inhibitors. On the other hand, agents that promote cell proliferation are also shown to accelerate the healing process. We will examine the effect of releasing 2-deoxy-D-ribose and melatonin, compounds shown to promote proliferative processes while the hydrogel concurrently suppresses inflammation. Keywords. Hydrogels, chronic wounds, antimicrobial, wound healing, matrix metalloproteinase